Pharmacology: Test 3: Antiplatelet, Anticoagulant And Thrombolytic Drugs

Front 1

What's the aim of preventing and reversing abnormal hemostasis?

Back 1

inhibit primary and secondary hemostasis and activate fibrinolysis via plasmin to breakdo insoluble fibrin.

Front 2

Antiplatelet dru do what?

Back 2

blcok signaling systmes that trigger platelet activation or proteins that mediate their adhesion or aggregation.

Front 3

What are the major drug targets

Back 3

Cyclooxygenase I (synthesizer for Thromboxane A2 (a vasoconstrictor and platelet activator/aggregator)).

The ADP receptor

The GPIIb/IIIA surface antigen, which bind fibrinogen and promote aggregation.

Front 4

Aspirin (acetylsalicylic acid, ASA)

Back 4

irreversibly inhibits COX1 for life of platelet (7-10 dz) whom can't synthesize new protein. They can't synthesize Thromboxane A2 (TXA2).

Decreases: risk of CHD, prevent strokes and stroke related mortality in ischemic stroke.

Used in Tx of unstable angina.

Negatives: GI bleeding and peptic ulcers.

Use 81mg baby aspirin. Higher dose doesn't provide additional antiplatelet activity but enhances side effects.

Front 5

Thienopyridine class: The ADP receptor antagonists

Back 5

are PRO drugs: clopidogrel (plavix), ticlopidine (ticlid).

P2Y1, P2Y12-R Irreversible antagonists

Drug of choice in pts allergic to aspirin.

Normally used in combo with aspirin. Slow onset b/c requires activation of pro drugs by p450 (3-5dz), peak efficacy at 8-11dz.

No benefit over aspirin alone but increased risk of bleeding and higher cost.

side effects: neutropenia and thrombocytopenia, monitor pts on this therapy.

2nd highest selling drug in the world!

Front 6

How does ADP-R antagonist work.

Back 6

Normally acitvation of P2Y1 and 12 receptors on platelet surface increases IP3 and decrease cAMP; both signals promote GPIIb/IIIa (fibrinogen receptor) on surface.

thienopyridine drugs block this from happening.

Front 7

Dipyridamole

Back 7

increases cAMP by inhibition of cAMP phosphodiesterase... so simila effect as thienopyridines (via blocking signals that promote expression of GPIIb/IIIa).

Different than thienopyridines in that it is also a VASODILATOR, and its efficacy is SUPERIOR to aspirin alone.

indicated as propylaxis of thromboemboli in heart valves, recurrence of stroke.

Front 8

Role of fish oils as antiplatelet drug

Back 8

unlike other fats, causes production of Thromboxane 3 (TXA3) which is a VASODILATOR, and also blocks platelet activation and aggregation.

Requires intact Cox enzyme, so aspirin would prevent TXA3 synthesis.

Front 9

Parenteral Antiplatelet Drugs: abciximab, eptifibatide, tirofiban

Back 9

abciximab: Fab fragement of antibody against GPIIb/IIIa which mediates platelet adhesion and aggregation. Abciximab block platelet-vasculature interraction for upto a day.

IV during angioplasty, reduce risk of re-stenosis. Expensive.

Eptifibatide: cyclic peptide, also inhibits GPIIb/IIIa.

Tirofiban: reversible, non-peptide inhibitor of GPIIb/IIIa.

Front 10

Pharm of coagulation cascade

Back 10

Secondary hemostasis, formation of fibrin clot, is targeted. Anticoagulants block acitivity or synthesis of: antithrombin, thrombin, and vitamin K epoxide reductase.

Front 11

Activities inhibited by Heparin?

Back 11

It inhibits the active forms: i.e. XIIa, XIa, IXa, Xa, IIa (thrombin)

Front 12

Activities inhibited by LMWH?

Back 12

Xa

Front 13

Synthesis inhibited by Warfarin?

Back 13

VII, IX, X, II (prothrombin)

Front 14

What labs are used for heparin and warfarin

Back 14

Use intrinsic pathway (PTT or aPTT) for Heparin.

Use extrinsic pathway (PT) for Warfarin. INR for PT is the standard.

Front 15

Heparin and Heparin Sulfate

Back 15

natural compound secreted by mast cells. Consist of neg. charged mucopolysaccharides.

Front 16

Heparin: Mech of action

Back 16

Normally antithrombin III, glycoprotein secreted by liver, binds thrombin (IIa) with low affinity.

Heparin act as an ENZYMATIC surface, allows antithrombin and thrombin plus other factors to 'meet' alteast with a thousand fold increase.

Antithrombin III makes a 1:1 complex with thrombin or the other coagulation factors, and are both permanently out of commission. Heparin can leave and catylyze formation of additional complexes.

Antithrombin III inhibits factors Xa, IXa, XIa, XIIa and Kallikrein but not factor VII.

Front 17

Heparin vs. Low Molecular Weight Heparin: What's the difference

Back 17

Heparin has a 18 monosaccharide units or larger which is required for Factor, Heparin and Antithrombin III (all 3 components) to come together all at once.

However, Factor Xa doesn't require the 3 components to come together all at once.

This is important b/c LMWH doesn't have the 18 units but rather only 5 monosaccharide units and can not bind antithrombin (IIa).

Front 18

Mech of action: LMWH

Back 18

It induces a conformational change in antithrombin III exposing the reactive site to Factor Xa.

So it only inhibits Factor Xa, and not thrombin (IIa) or the other factors.

Front 19

Pharmacokinetics: Heparin and LMWH

Back 19

Heparin: half life increases with increasing doses b/c of both saturable and unsaturable processes (complicated pharmakokinetics).

LMWH: greater bioavailability, longer plasma half-life, and simpler pharmkokinetics. Self-admin. syringes available.

Front 20

Heparin Administration?

Back 20

NEVER give I.M. b/c risk of hematoma

Dose Unit: amt of hep needed to prevent 1 ml sheep plasma from clotting for 1 hr following addition of .2 ml of CaCl2.

LD: 5000-10000 U as I.V. w maint dose: 900-1600 U/hr.

Can be SQ at 5000 U per 8-12 hrs.

Goal: get aPTT 1.5 to 2.5x. Not monitored with LMWH.

Large Dose req'd for pulmonary embolism due to increased heparin clearance.

Front 21

Heparin Toxicity

Back 21

Bleeding

transient thrombocytopenia: assoc w/ paradoxical thrombotic complications b/c thrombocytopenia is an immune reaction and results in IgG mediated platelet activation. Less freq w/ LMWH

Can be used during pregnancy w/ caution: no placenta crossing.

Front 22

Heparin Clinical indications

Back 22

First line: prev and tx of venous thromboembolism

i.e following post surgeries MIs etc.

Front 23

Some LMWH?

Back 23

enoxaparin, dalteparin, tinzaparin (all end in -parin).

Enoxaparin and dalteparin following hip repl or abd surgeries.

also recomm for prev of recurrent angina or MIs.

Front 24

Heparin contraindications?

Back 24

pts undergoing brain, sp. cord, or eye surgery bc even minor bleeding may cause major problems.

Front 25

Heparin antidote

Back 25

mild bleeding reversed by mere termination of therapy within hours.

Severe bleeding due to heparin: use PROTAMINE SULFATE.

basic protein tightly binds and neutralizes heparin (which is acidic).

Protamine sulfate has weak anticoagulant effects so use minimal dose (1 mg for every 100 U of heparin).

Front 26

Fondaparinux

Back 26

first synthetic selective inhibitor of factor Xa. Indiacted by prophylaxis of deep vein thrombosis.

Front 27

Lepirudin, bivalirudin

Back 27

reversible, direct thrombin inhibitors.

from salivary glands of leeches.

cleared by kidney so use w/ caution in pts with renal failure. Monitor aPTT.

Front 28

Argatroban

Back 28

also direct reversible thrombin inhibitor. But different from 'iuridins' in that cleared by Hepatic 450. Monitor aPTT.

Front 29

Coumadin

Back 29

most freq. used oral anticoagulant.

Front 30

Coumadin: Mech of Action

Back 30

glutamate residues of factor II, VII, IX and X undergo carboxylation to turn inactive decarboxy- form of proteini into active coag factors. Vit K is a cofactor for decarboxylation during which it goes from hydroquinone form to an epoxide.

Coumadin inhibits conversion of the epoxide form of VitK back to hydroquinone form, therefore resulting in depletion of this cofactor.

No effect on synthesis of the coag cofactors, just prevents their activation.

Front 31

Coumadin Pharmakokinetics

Back 31

nearly 100% bioavailability but highly plasma albumin bound (99%).

small VD and long plasma half life.

inactivated by kidney and liver.

S-form 4x more potent than R-form.

Front 32

Coumadin Administration

Back 32

no need for LD b/c of its mech of action. Started off with small initial doses and increased as indicated by PT/INR.

No effect on carboxylated coag factors. Therefore, degradation rate of coag factor will determine when drug exerts its full effect. PT quickly prolonged due to faster breakdown of Factor VIII.

Primary aim: prolong PT to 25% of normal clotting activity. Translates to INR of 2.5-3.5 (PT of 1.6).

Front 33

Coumadin: clinical indications

Back 33

Acute MI: preve of stroke or pulm embolism

Prev of stroke

Atrial fibrillation: reduce stroke rate

Prosthetic heart valve: reduce thromboembolims

Prophyl. or tx of venous thromboembolism

Front 34

Drug Interraction: Warfarin

Back 34

DO NOT USE IN PREGNANCY.

See p. 8, lect 45 and 46.

Front 35

Coumadin: Contraindication

Back 35

birth defects and abortion, do not use in pregnancy.

Extreme caution in pts with hepatic or renal dz or GI tract lesion.

Front 36

Clot busters

Back 36

Thrombolytics enhance fibrinolysis by promoting covernsion of plasminogen to plasmin.

Front 37

Thrombolytic drugs

Back 37

urokinase, streptokinase, anistreplase, tissue plasminogen activator (t-PA).

t-PA does not induce system activation, activates plasminogen to plasmin only in presence of fibrin.

Front 38

Thrmobolytic drugs: indications

Back 38

multiple pulmonary emboli, central DVTs, acute MI in only selected pts

Contraindicated for: surgery, GI tract bleeding, aneurysm, hypertension, active bleeding etc.